As the gut microbiota exerts various effects on the intestinal milieu which influences distant organs and pathways, it is considered to be a full-fledged endocrine organ. The microbiota plays a major role in the reproductive endocrine system throughout a woman’s lifetime by interacting with estrogen, androgens, insulin, and other hormones. Imbalance of the gut microbiota composition can lead to several diseases and conditions, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome (PCOS), endometriosis, and cancer; however, research on the mechanisms is limited. More effort should be concentrated on exploring the potential causes and underlying the mechanisms of microbiota-hormone-mediated disease, and providing novel therapeutic and preventive strategies.As the gut microbiota exerts various effects on the intestinal milieu which influences distant organs and pathways, it is considered to be a full-fledged endocrine organ. The microbiota plays a major role in the reproductive endocrine system throughout a woman’s lifetime by interacting with estrogen, androgens, insulin, and other hormones. Imbalance of the gut microbiota composition can lead to several diseases and conditions, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome (PCOS), endometriosis, and cancer; however, research on the mechanisms is limited. More effort should be concentrated on exploring the potential causes and underlying the mechanisms of microbiota-hormone-mediated disease, and providing novel therapeutic and preventive strategies.

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases among women of reproductive age and is associated with many metabolic manifestations, such as obesity, insulin resistance (IR) and hyperandrogenism. The underlying pathogenesis of these metabolic symptoms has not yet been fully elucidated. With the application of metabolomics techniques, a variety of metabolite changes have been observed in the serum and follicular fluid (FF) of PCOS patients and animal models. Changes in metabolites result from the daily diet and occur during uncommon physiological routines. However, some of these metabolite changes may provide evidence to explain possible mechanisms and new approaches for prevention and therapy. This article reviews the pathogenesis of PCOS metabolic symptoms and the relationship between metabolites and the pathophysiology of PCOS. Furthermore, the potential clinical application of some specific metabolites will be discussed.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus–pituitary–ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfunction and abnormal sex steroids synthesis. By contrast, peripheral sex steroids can modulate the action of GnRH neurons through a feedback effect, which is impaired in PCOS, thus forming a vicious cycle. Additionally, hypothalamic GnRH neurons not only serve as the final output pathway of central control of reproductive axis, but also as the central connection point where reproductive function and metabolic state inter-regulate with each other. Metabolic factors, such as insulin resistance and obesity in PCOS patients can regulate GnRH neurons activity, and ultimately regulate reproductive function. Besides, gut hormones act on both brain and peripheral organs to modify metabolic state. Gut microbiota disturbance is also related to many metabolic diseases and has been reported to play an essential part in PCOS development. This review concludes with the mechanism of central modulation and the interaction between neuroendocrine factors and reproductive or metabolic disorders in PCOS development. Furthermore, the role of the gut microenvironment as an important part involved in the abnormal neuronal–reproductive–metabolic circuits that contribute to PCOS is discussed, thus offering possible central and peripheral therapeutic targets for PCOS patients.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota–host cross-talk. We developed an enzyme activity–screening platform to investigate how gut microbiota–derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.